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Metabolic Effects of High-Protein,Low-Carbohydrate Diets

Margo A. Denke, MD

Weight-losing diets appeal to the growing popu-lation of overweight Americans. Fad diets

promise rapid weight loss, easy weight loss, limitedrestrictions on portion sizes of favorite foods, andabove all an enhanced sense of well being. The pop-ularity of fad diets points out the honest promises oftraditional weight loss diets. Traditional weight lossdiets promise slow weight loss of 0.45 to 0.9 kg/week.The weight loss is nothing but easy, because portionsizes of nearly all foods except low-calorie freefoods must be continuously evaluated and tracked.Claiming an enhanced sense of well being is hardlyappropriate for a traditional dietmost patients reportdissatisfaction from the constant vigilance over di-

etary intake. Through discipline and perseverance,traditional weight loss programs try to teach a patienta new lifestyle of healthy eating. Unfortunately, 70%of successful weight losers return to their old habitsand within 2 years regain at least half of the weightlost. These patients typically have little insight into thereasons why the weight was regained, and considerthemselves failures to traditional diet programs.They become prime targets for diets promising rapidand easy weight loss.

PROTOTYPES OF THE HIGH-PROTEIN,LOW-CARBOHYDRATE DIETS

High-protein, low-carbohydrate diets have a long his-tory of cyclic popularity. Greek Olympians ate highmeat, low vegetable diets 2,000 years ago to improveathletic performance. Dr. William Harvey recommendeda diet prohibiting sweet and starchy foods and permittingad lib consumption of meats for patients who neededdiuresis. As the basic understanding of nutrition andessential vitamins developed, these diets fell out of favor.They regained popularity in the late 1960s and early1970s with the publication of the Atkins Diet, StillmansDiet, The Drinking Mans Diet, the Scarsdale Diet, andthe Air Force Diet. The American Medical Associationstrongly criticized these diets,1 leading to their submer-

gence on the popular diet trend.Resurgence of low carbohydrate diets has been

fueled by rising obesity and insulin resistance in thegeneral population. Although the Atkins Diet is theprototype of the low carbohydrate diet, The SugarBusters Diet, Carbohydrate Addicts Diet, Protein

Power Diet, and the Zone Diet are all variations onthis common theme.

Several diets promise that, as long as you restrictcarbohydrates, you will lose weight and you can eat asmuch food as you want. There may be a kernel of truthto this claim. For some patients, high-protein intakesuppresses appetite.2 For other patients, ketosis fromcarbohydrate restriction suppresses appetite. Restrict-ing carbohydrate eliminates some popular foods thatare often consumed in excess such as bread, cereal,soft drinks, french fries, and pizza. By simply exclud-ing carbohydrate foods, patients following the Atkinsdiet typically consume 500 fewer calories a day.3

HOW LOW-CARBOHYDRATE DIETSPRODUCE INITIALLY GREATER

WEIGHT LOSSReducing caloric intake by 500 kcal/day should

result in a 0.45- to 0.9-kg weight loss each week.However, low-carbohydrate, high-protein diets typi-cally produce a 2- to 3-kg weight loss in the first week.This added weight loss is not due to the miracle ofswitching the bodys metabolism over to burning fatstores. It is due to a diet-induced diuresis. Whencarbohydrate intake is restricted, 2 metabolic pro-cesses occur, both of which simultaneously reducetotal body water content. The first process is mobili-

zation of glycogen stores in liver and muscle. Eachgram of glycogen is mobilized with approximately 2 gof water. The liver stores approximately 100 g ofglycogen and muscle has 400 g of glycogen. Mobili-zation glycogen stores result in a weight loss of ap-proximately 1 kg. Patients notice this change as areduction in symptoms of bloating and are verypleased with the effect. The second process is gener-ation of ketone bodies from catabolism of dietary andendogenous fat. Ketone bodies are filtered by thekidney as nonreabsorbable anions.4 Their presence inrenal lumenal fluids increase distal sodium delivery tothe lumen, and therefore increase renal sodium and

water loss.In a study comparing an 800-calorie mixed diet with

an 800-calorie low-carbohydrate, high fat diet,5 10-dayweight loss was 4.6 kg on the ketogenic diet and 2.8 kgon the mixed diet. Energy-nitrogen balanced studies doc-umented that the difference in weight lost was all ac-counted for by losses in total body water.

LONG-TERM WEIGHT LOSS ISINFLUENCED BY CALORICRESTRICTION, NOT CARBOHYDRATERESTRICTION

The diuretic effect of low-carbohydrate intake is

limited to the first week of the diet. The remaining

From the Division of Endocrinology and Center for Human Nutrition,University of Texas Southwestern Medical Center at Dallas, Dallas,Texas. Manuscript received October 16, 2000; revised manuscriptreceived and accepted February 6, 2001.

Address for reprints: Margo A. Denke, MD, Center for HumanNutrition, The University of Texas Southwestern Medical Center atDallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052.

E-mail: mdenke@mednet.swmed.edu.

592001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$see front matterThe American Journal of Cardiology Vol. 88 July 1, 2001 PII S0002-9149(01)01586-7

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weight loss is a function of the laws of energy balance.Calories from any source determine the success ofadditional weight loss.

In the only published study of Atkins diet, pa-tients following the diet reduced caloric intake by500 kcal/day. The average weight loss was 7.7 kg at8 weeks, which is no greater than that expectedfrom caloric restriction alone.6 The ability of low

carbohydrate intake to generate ketones has beentouted as a relative advantage for losing weight.However, this advantage was not confirmed in a1-month study comparing ketogenic with nonketo-genic hypocaloric diets.7 Most comparison studieshave evaluated the relative advantages of either alow carbohydrate or low fat hypocaloric diets; somestudies found a slight 1- to 3-kg greater weight losson a low-carbohydrate diet,8,9,10,11 others a slightadvantage with a high-carbohydrate diet,12 but moststudies have observed no statistical advantage of alow-carbohydrate diet.1318 The preponderance ofevidence suggests that as long as caloric intake

remains constant,19 there is no intrinsic advantageto cutting carbohydrate intake.20

UNTOWARD METABOLIC EFFECTSComplications from ketosis:Eucaloric ketogenic di-

ets have been prescribed as part of an antiepilepticregimen in children with refractory seizure disorders.Children following these ketogenic diets have higherrates of dehydration, constipation, and kidney stones.Other reported adverse effects include hyperlipidemia,impaired neutrophil function, optic neuropathy, osteo-porosis, and protein deficiency.21

Because ketogenic diets effect the central nervoussystem, it has been suspected that ketogenic diets mayalter cognitive function. In a randomized weight lossstudy comparing a ketogenic with a nonketogenichypocaloric diet, subjects consuming the ketogenicdiet had impairments in higher order mental process-ing and flexibility than those following the nonketo-genic diet.7

Complications from high saturated fat intake: De-spite the beneficial effects of weight loss, diets thatpromote liberal intake of high fat meats and dairyproducts raise cholesterol levels. In a study 24 sub-

jects following the Atkins-type 4-week inductiondiet, then 4 weeks maintenance diet,6 low-densitylipoprotein cholesterol levels increased significantlyfrom 127 to 151 mg/dl. Similar increases in totalcholesterol (13%) were reported in a study of patientsfollowing the Stillman diet.22

Complications from high fat intake: High fat dietsincrease free fatty acid flux and circulating free fattyacids. Fasting plasma free fatty acids may have apro-arrhythmic effect in cardiac muscle. A number ofmechanisms have been suggested including a possibledetergent effect of circulating free fatty acids on cellmembranes and direct effects of acylcarnitine on cel-

lular ion channels and exchangers.

Complications from exclusion of fruits, vegetables,and grains: Because they exclude fruits, vegetables,and grains, low-carbohydrate, high-protein diets aredeficient in micronutrients. Children consuming low-carbohydrate ketogenic diets have reduced intakes ofcalcium, magnesium, and iron.21 Two sailors follow-ing a low-carbohydrate, high-protein hypocaloric dietduring an extended voyage developed optic neuropa-thy from thiamine deficiency.23 Although vitamin de-ficiencies can be circumvented by supplemental mul-tivitamins, even supplemented low-carbohydrate dietswill still be deficient in a growing number of impor-tant, biologically active phytochemicals present infruits, vegetables, and grains.

Complications from high-protein intake: Increasingthe protein content of a diet significantly increasesglomerular filtration rate.24,25 Increases in glomerularfiltration rate are likely explained by increased renalcapillary permeability. Unfortunately, this compensa-tory response to the greater production of nitrogen isinsufficient to clear protein by-products, and bloodurea nitrogen levels increase. High protein diets sig-

nificantly lower urinary pH by increasing titratableacid concentrations.25,26 High protein intakes providea greater uric acid load to the kidney. Despite in-creases in urinary uric acid excretion, increases inserum uric acid are observed.6,26

UNTOWARD LONG-TERM EFFECTSDevelopment of nephrolithiasis: Hypercalciuria is a

risk factor for nephrolithiasis. High-protein diets in-duce hypercalciuria by several different mechanisms.High-protein diets increase glomerular filtration rateand decrease renal tubular reabsorption of calcium.The relation between dietary protein intake and cal-

cium excretion (Table 1) is clearly linear.27The stone-forming propensity of the hypercalciuria

induced by high-protein diets is aggravated by otherchanges in urine composition. A high animal proteindiet reduces gastrointestinal alkali absorption, leadingto reduced urinary citrate.28 Hyperuricemia and hyper-uricosuria are also associated with excess intake ofanimal protein. Animal protein is a rich source ofsulfur-containing amino acids; amino acids have agreater propensity to lower urinary pH.

Adding a carbohydrate restriction to a high-proteindiet exacerbates many of these parameters. Low-car-bohydrate intake further reduces urinary pH by induc-

ing ketosis. Limiting the intake of vegetables andfruits further reduces urinary citrate by reducing di-etary sources of alkali. Thus, high-protein, low-carbo-hydrate diets are associated with hypercalciuria, hy-peruricosuria, and hypocitraturia, which can all con-tribute to renal calculi formation.

Development of osteoporosis: High-protein, low-carbohydrate diets generate a high acid load, resultingin a subclinical chronic metabolic acidosis. Metabolicacidosis promotes calcium mobilization from bone.29

Osteoclasts and osteoblasts respond to small changesin pH in cell culture; thus, a small decrease in pHresults in a large burst of bone resorption.

The effects of varying dietary protein intakes on

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bone turnover has been carefully documented inyoung women consuming metabolic diets. High-pro-tein diets increase renal calcium excretion, raisedparathyroid hormone levels, and raise urinary N-te-lopeptide concentrations. Markers of bone formation(alkaline phosphatase and osteocalcin) remain steady,suggesting that high-protein diets increase bone re-sorption without affecting the rate of bone forma-tion.27 These effects may be exaggerated in olderpersons who tend to have decrements in renal clear-ance of acid and higher serum parathyroid hormoneconcentrations.29

Progression of chronic renal insufficiency:In severalsmall, randomized, controlled dietary trials, dietaryprotein restriction retarded the progression of diabeticnephropathy to end-stage renal disease.30 High-pro-tein, low-carbohydrate diets have a weak effect atreducing creatinine clearance over time, and couldpotentially hasten renal failure in patients with base-line renal insufficiency.

Patients are inherently attracted to the simple, permis-sive dietary instructions: eat as much as you want offoods containing fat and protein, but dont eat foodscontaining carbohydrate. As promised, almost everyoneloses weight during the first week. Low-carbohydratediets cause a greater initial weight loss from a physio-logic diuresis accompanying the obligate loss of glyco-gen stores and renal clearance of ketone bodies. Onceglycogen stores have been liberated, and a new steadystate for total body sodium has been achieved, these dietshold no greater promise for weight loss than any othercaloric restricted diet. High-fat, low-carbohydrate dietscan be harmful. The diet plan is deficient in micronutri-

ents. Consuming ad libitum fatty meats raises total andlow-density lipoprotein cholesterol levels. High-protein,low-carbohydrate intakes create a subclinical metabolicacidosis, and increase blood urea nitrogen and uric acidlevels. Resultant urine acidification, hyperuricosuria, andhypercalciuria increase urine lithogenicity. Trying toconvince a devotee to stop the diet uncovers yet anotherdeleterious effect; ketogenic diets impair higher ordercognitive function. High-protein, low-carbohydrate dietshave untoward clinical consequences for patients withcoronary artery disease, including progression of diabeticnephropathy, exacerbation of gouty diathesis, increasesin circulating free fatty acids, and increases in low-

density lipoprotein cholesterol levels. High-protein, low-

carbohydrate diets are not superiorweight-losing diets and should not berecommended.

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TABLE 1 Graded Effects of High-Protein Diets on Urinary Calcium Excretion

DietDuration

% Calories fromProtein* No.

Creatinine Clearance(ml/min)

Urinary Calcium Excretion(mg/24 h)

Low Medium High Low Medium High

15 d 1%/12%/25% 6 98 105 122 51 99 1614 d 8%/12%/25% 16 85 95 107 108 129 196

15 d 8%/16%/24% 33 168 240 301

15 d 8%/16%/24% 9 217 303 426

15 d 8%/16%/24% 9 168 240 301

*Percent calories calculated assuming 70-kg average subject weight, 2,400-calorie diet.Significantly different from low-protein diet.

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